The present invention generally relates to the treatment of metallic surfaces to enhance their biocompatibility and to medical devices and the like which include such biocompatible surfaces. More specifically, the invention relates to depositing a film of heptafluorobutylmethacrylate ("HFBMA") on a metallic surface using radiofrequency plasma deposition and subsequently functionalizing the deposited HFBMA by a water vapor radiofrequency plasma treatment. Biologically active agents are bound to the HFBMA coated surface so that medical devices which include such surfaces possess an improved biocompatibility.
Those skilled in the art will appreciate the importance of certain medical devices having surfaces of an enhanced biocompatibility. Medical devices made from polymeric materials as well as from metallic materials generally benefit from having enhanced biocompatibility especially where such devices are intended for subcutaneous implantation where they can experience in vivo environments depending on the nature of the particular device. The biocompatibility of such medical devices is generally enhanced by attempting to secure certain agents to the surface of those devices. For example, anti-thrombogenic agents are often secured to the surfaces of medical devices having blood contacting surfaces. It would be particularly undesirable to have the anti-thrombogenic agent leach away in wet environments such as those encountered by medical devices that engage blood or other body fluids.
Attempts have been made and approaches have been suggested for activating the surface of a medical device with a radiofrequency ("RF") plasma. The activated surface reacts with heparin or other biologically active agents to provide a biocompatible surface having specific characteristics such as Anti-thrombogenicity, endothelial growth promoters, and the like. The treatment of surfaces with a radiofrequency plasma has been described in various patents. Included are patents incorporating plasma discharge treatment with a gaseous environment including a variety of gases such as inert and organic gases. Patents in this regard include U.S. Pat. Nos. 4,613,517, 4,656,083 and 4,948,628, which mention a variety of plasma media including those generated from hydrogen, helium, ammonia, nitrogen, oxygen, neon, argon, krypton, xenon, ethylenic monomers and other hydrocarbons, halohydrocarbons, halocarbons and silanes. Certain of these plasma media are relatively expensive and can be hazardous to use within a manufacturing environment and/or to dispose of as waste. Certain plasma media are more suitable for treatment of specific substances.
Other surface treatments have been proposed specifically for metal surfaces intended to contact bodily fluids and the like during implantation. One such treatment involves the chemical oxidation of the metallic surface, such as a tantalum surface, until enough of a metal oxide layer is provided for bonding with a bioactive agent. Many other approaches in this area have concentrated on utilizing polymeric surfaces as the surface which encounters the body fluids and then treating those polymeric surfaces according to a variety of procedures. Polymeric surfaces and metallic surfaces each pose different problems which must be overcome to provide a polymeric or metallic surface that is suitable for implantation and/or extended-time residence within the body. U.S. Pat. Nos. 3,549,409 and 3,639,141 describe treatments of particular polymeric surfaces by swelling the polymeric surface, bonding an agent thereto and noncovalently coupling heparin to that agent. The latter of these patents mentions contacting the polymeric surface with an amino alkyl trialkoxysilane dissolved in an organic solvent to swell the polymeric material. Another approach involving a chemical treatment is exemplified by U.S. Pat. Nos. 4,526,714 and 4,634,762 which indicate that a surface can be rendered biocompatible by coating it with a conjugate of heparinous material and a protein, with the conjugate being formed by coupling carried out in the presence of 1-ethyl-3-dimethyl-aminopropyl carbodiimide (known as EDC) and the like as a coupling agent. The conjugate is attached to the substrate surface at the sites where the surface free functional groups suitable for bonding to the conjugate are present. In order to effect the coupling needed to form this conjugate, these free functional groups on the substrate surface are provided as free amino groups.
Another treatment procedure involves treatment of a surface with heparin benzalkonium chloride (HBAC). A quaternary amine structure is involved. The result is an ionic linkage, and subsequent ionic exchange occurs quite readily. For example, HBAC is easily leached from the treated surfaces to the extent that substantially all of the heparin is removed within about three days under leaching conditions. In addition, 4M guanidine, which is used to demonstrate the ionic nature of bonds by an ionic exchange mechanism, quickly removes the heparin in a one hour, non-physiological ionic release test. Furthermore, because benzalkonium chloride is in essence a surfactant, an HBAC conjugated surface is a cytotoxic material as well as a hemolytic material, causing a breakdown of red blood cells.
Other quaternary amine alternatives are believed to be non-hemolytic such as tetradodecylammonium chloride (TDAMC), for example. These types of materials are typically applied from a hydrocarbon solvent system, also providing ionic bonding and ionic exchange can and does occur quite readily. Because of its molecular structure, heparin and materials having similar functions do not escape quite as readily from TDAMC as from HBAC, but leaching is still very apparent. When attachment to a surface is by means of ionic bonding of TDAMC and the like, most of the heparin or bioactive agent is leached away after three hours of contact with blood plasma or after about 24 hours within a phosphate buffered saline solution under physiological conditions. The ionically attached material is substantially completely removed with guanidine within about one hour during non-physiological testing.
Many of the above-discussed attempts to improve the biocompatibility of various medical devices do not fare well under in vivo or biological conditions, and they fall short of fulfilling desirable attributes such as having the coating remain functional for a length of time adequate to provide maximum thrombus prevention. Another important consideration is whether the coating interferes with endothelialization. For metallic medical devices which undergo movements, such as bending of a portion thereof during implantation and/or use, the mechanical properties of the treatment coating should be able to withstand flexure during bending, expansion and the like of the coated member. For example, metallic radially expandable generally tubularly shaped endoprostheses which are generally known as stents, must be able to withstand such flexure. An exemplary stent is described in U.S. Pat. No. 5,019,090, the subject matter thereof being incorporated by reference hereinto. Such stents are made of a very fine gauge metallic wire, typically tantalum or stainless steel wire. During implantation, these stents are mounted onto the balloon of an angioplasty catheter or the like until a partially occluded location within the blood vessel is reached, at which time the balloon and the stent are radially and circumferentially expanded for purposes of opening the occlusion and supporting the vessel at that location. This necessarily involves rather extensive bending of the tantalum wire. Many previously available coatings do not have the flexibility and/or adherence properties needed to avoid cracking and/or loss of the coating when subjected to this type of flexure.
It would be desirable to design and utilize a system which meets the objectives of imparting biocompatibility to a metallic substrate to thereby substantially prevent thrombus formation on the metallic surface. Such a system should not crack or otherwise deteriorate due to mechanical movement of the treated metallic member and the system should not allow substantial leaching of the biologically active material and should not substantially interfere with endothelialization after in vivo implantation.
It has been determined that a system providing covalent linkages between a bioactive agent and a functionalized HFBMA coated metal surface meets these objectives, providing an enhanced metallic surface with permanently improved biocompatibility. Such a system includes treating a metallic surface of the medical device with an RF plasma to deposit a film of HFBMA and subsequently functionalizing the deposited film by water vapor plasma treatment, thus providing available carboxy and hydroxy groups on the HFBMA coating to facilitate bonding with bioactive agents. The bioactive agents can be bound to the HFBMA surface using different reaction schemes and reagents including without limitation carbodiimide chemistry, organosilane chemistry, Woodwards K reagent and glutaraldehyde cross-linking. Various anti-thrombogenic agents, endothelial growth promoters, smooth muscle cell anti-proliferative agents, platelet growth factor antagonists, vasoconstrictors and vasodialators and cellular adhesion promoters can all be applied alone or in combination with spacers such as albumin, polyethylene oxide, various diacid chlorides, polyethyleneimine, N-(2-aminoethyl-3-aminopropyl) trimethoxysilane and the like.
The activated HFBMA-modified metallic surface may be treated with either a spacer or the bioactive agent using carbodiimide chemistry utilizing a water soluble carbodiimide. The molecule attached to the surface (either the HFBMA or the spacer) must have a primary or secondary amine and for a spacer there must be at least two primary or secondary amines. Endovascular stents can be made using these HFBMA coated metallic surfaces. There is evidence to show that a completely and quickly endothelialized object, such as a stent, does not promote smooth muscle cell proliferation and therefore could prevent restenosis.
It is accordingly a general object of the present invention to provide an improved biocompatible metallic surface, a method of preparing such a surface and a method of implanting a device having such a surface.
Another object of the present invention is to provide an improved stent or other medical device having a HFBMA coating which is capable of covalently bonding to bioactive agents and is able to withstand flexure and interaction with fluids.
Another object of this invention is to provide a method for depositing a film of HFBMA by radiofrequency plasma deposition and binding a bioactive agent thereto to provide an enhanced metallic surface with permanently improved biocompatibility.
Another object of the present invention is to provide an improved metallic surface which is particularly compatible and exhibits advantageous properties conducive to long-term placement within a body.
Another object of the present invention is to provide a treatment for metallic surfaces without detrimentally affecting the mechanical properties of the metal.
These and other objects, features and advantages of the present invention will be clearly understood by those skilled in the art through a consideration of the remainder of the disclosure, including the drawings and the detailed description of the preferred embodiments.